Peroxisome proliferation factor activated receptor (PPAR) and glucocorticoid receptor, tretinoin receptor and thyroxine receptor belong to ligand dependent transcription factor of nuclear receptor superfamily. Up to now, it has been found that PPARs have three subtypes: α, γ and δ (also called as β), which are encoded by different genes. Moreover, due to the difference of promoter and jointing manner, PPARγ is also divided into two isoforms: γ1 and γ2, both are different only in the sequence of N end (Visal-Puig, J. Clin. Invest., 97: 2553-2561, 1996). When activated by specific small molecules, PPARs can interact with PPARs reaction elements (PPRE) in promoter region of target gene to modulate the expression of the gene. PPARs is an important transcription modulation factor of metabolism of glucose, lipids and cholesterols in vivo.
PPARα is primarily expressed in the tissue exhibiting rather high decomposition and metabolism activity, such as brown fat tissue and liver, and secondly expressed in kidney, heart and skeletal muscle (Endocnnology, 1995, 137, 354). It can positively or negatively control the expression of genes related to fatty acid metabolism and intra-cellular conveying (e.g. acetyl CoA synthase, fatty acid binding protein and lipoprotein lipase) and apoprotein (AI, AII, CIII) genes related to the metabolism of cholesterol and neutral lipids. PPARγ is mainly present in fat tissue and also present in small quantity in skeletal muscle, liver, colon, retina, immune system. Recently study results show that it is highly expressed in macrophages, including foam cells of atherosclerosis. PPARγ2 is mainly exclusively expressed in fat tissue, while PPARγ1 has been found in various tissues, in which the expression in kidney, intestines and heart is the highest. PPARγ mainly modulates the expression of genes related to fatty cells differentiation and insulin sensitivity (J. Lipid. Res., 1996, 37, 907). PPARδ is distributed widely and expressed in many tissues, wherein the expression in intestines, kidney, heart is the highest. The activation of PPARδ has shown the increase of HDL level and reduction of LDL and VLDL level.
Thiazolinediones drugs, such as, rosiglitazone, show in clinic the enhancement of insulin of diabetes type II patients, reduction of serum glucose. It has been reported thiazolinediones are effective and selective activators of PPARγ and directly bind to PPRRγ (J. M. Lehmann, et al. J. Biol. Chem. 12953-12956, 270 (1995)).
Fibrates drugs have been widely used as therapeutic agents of hyperlipidemia. They can reduce serum triglyceride (20-50%), LDLc (10-15%), and increase HDLc (10-15%). Experiments have shown that the action of fibrates to serum lipids is mediated by activation of PPARα, see, e.g. B. Staels, et al. Curr. Pharm. Des., 1-14, 3(1), (1997). The activation of PPARα leads to the transcription of enzymes that increase the decomposition and metabolism of fatty acids and decrease the resynthesis of fatty acids in liver (causing the reduction of the synthesis of triglyceride and production/secretion of VLDL). Besides, PPARα activation reduces the production of apoC-III. The reduction of the production of apoC-III (an inhibitor of LPL activity) increases the clearance of VLDL (J. Auwerx, et al, Atherosclerosis, J59-S37, 124 (Suppl), (1996)).
PPAR is related to many biological courses and diseases conditions, including hypercholesterolemia, dyslipidemia and diabetes. However, the action of present drugs is not ideal due to toxic and side-effect. Therefore, a safe and effective PPAR agonist drug is needed, which can selectively activate one subtype, or activate multiple subtypes simultaneously.